The long-term goal of the parent grant "Assembly of inward rectifier K channels [DK02389] has been to understand the molecular basis of inward rectifier potassium (Kir) channel subunit interactions. The diversity of Kir channels encompasses a multitude of cellular processes: maintenance and modulation of membrane electrical activity, receptor-mediated changes in membrane potential and excitability, formation of ionic pathways for K+ secretion in epithelial cells, and coupling of cellular metabolism directly to membrane electrical events [underlying such processes as, pancreatic beta-cell insulin secretion, ischemia-induced neuronal and cardiac cellular responses, regulation of vascular smooth muscle tone]. Remarkably within less than three years, new Kir channel genes and subfamilies, revelations of heteromultimeric Kir channels and of subunit stoichiometry, the cloning of sulfonylurea receptors (SUR family) with the reconstitution of ATP-sensitive (KATP) K+ channels, as well as, new milestones in our understanding of the biophysics and regulatory interactions of Kir channels and their associated proteins, have resulted in a pace-setting new field in biophysics and molecular physiology. Indeed, the importance of this project's aims have been spectacularly demonstrated. This research program will therefore expand its focus to elucidate the maturation and assembly of Kir channels, Kir6.2 [KATP] and Kir1.1 [ROMK] in relation to the biogenesis of their associated ATP-binding cassette (ABC) transporter/channel proteins [respectively, the sulfonylurea receptor, SUR, and cystic fibrosis transmembrane conductance regulator, CFTR] and cellular proteins facilitating these processes. Mutations in these same channel proteins result in the disorder of glucose homeostasis, persistent hyperinsulinemic hypoglycemia of infancy (Kir6.2 and SUR1); the salt-wasting disorder, Bartter's syndrome (Kir1.1a), and the lethal inherited disorder, cystic fibrosis (CFTR). An understanding of the biogenesis of these channel proteins will aid not only in the elucidation of the molecular events underlying each of these diseases, but may also provide insights into the development of novel therapeutic strategies.